Table 2.
Summary of PK parameters of probe drugs with and without rucaparib
| PK parameters by probe drug | Patients, n | Geometric mean (%CV)a | Ratio (90% CI) | |
|---|---|---|---|---|
| Without rucaparib | With rucaparib | |||
| Caffeine | ||||
| Cmax (ng/mL) | 16 | 5980 (30) | 5900 (16) | 0.99 (0.90–1.08) |
| AUC0–72h (ng·h/mL) | 16 | 57,500 (61) | 130,000 (34) | 2.26 (1.93–2.65) |
| AUC0–inf (h ng·h/mL) | 11 | 59,300 (76) | 152,000 (31) | 2.55 (2.12–3.08) |
| t1/2 (h) | 11 | 7.0 (78) | 20.7 (25) | – |
| tmax (h) | 16 | 0.5 (0.3, 2.0) | 1.0 (0.5, 2.0) | – |
| S-warfarinb,c | ||||
| Cmax (ng/mL) | 14 | 721 (20) | 759 (20) | 1.05 (0.99–1.12) |
| AUC0–96h (h*ng/mL) | 14 | 20,300 (26) | 30,200 (29) | 1.49 (1.40–1.58) |
| tmax (h) | 14 | 1.0 (0.5, 3.0) | 1.5 (0.5, 3.0) | – |
| Omeprazole | ||||
| Cmax (ng/mL) | 16 | 1110 (71) | 1210 (54) | 1.09 (0.93–1.27) |
| AUC0–72h (ng·h/mL) | 16 | 2910 (123) | 4510 (116) | 1.55 (1.32–1.83) |
| AUC0–inf (ng·h/mL) | 16 | 2920 (123) | 4540 (116) | 1.55 (1.32–1.83) |
| t1/2 (h) | 16 | 1.5 (91) | 2.3 (91) | – |
| tmax (h) | 16 | 2.0 (1.0, 3.0) | 2.0 (2.0, 3.0) | – |
| Midazolam | ||||
| Cmax (ng/mL) | 16 | 19.4 (35) | 22.0 (54) | 1.13 (0.95–1.36) |
| AUC0–72h (ng·h/mL) | 16 | 45.4 (65) | 63.0 (69) | 1.39 (1.14–1.68) |
| AUC0–inf (ng·h/mL) | 16 | 48.0 (64) | 66.5 (67) | 1.38 (1.13–1.69) |
| t1/2 (h) | 16 | 6.8 (41) | 7.8 (39) | – |
| tmax (h) | 16 | 0.5 (0.3, 1.0) | 0.5 (0.2, 2.0) | – |
| Digoxinb,c | ||||
| Cmax (pg/mL) | 16 | 1940 (34) | 1860 (32) | 0.96 (0.84–1.10) |
| AUC0–72h (pg·h/mL) | 16 | 21,500 (20) | 25,900 (27) | 1.20 (1.12–1.29) |
| tmax (h) | 16 | 1.0 (0.5, 3.0) | 1.0 (0.5, 3.0) | – |
| Rosuvastatin | ||||
| Cmax (ng/mL) | 18 | 13.0 (116)d | 18.1 (107)e | 1.29 (1.07–1.55) |
| AUC0–last (ng·h/mL) | 18 | 145 (95.9)d | 200 (95.9)e | 1.34 (1.16–1.54) |
| AUC0–inf (ng·h/mL) | 18 | 145 (94.0)e | 210 (93.0)e | 1.35 (1.17–1.57) |
| t1/2 (h) | 18 | 17.5 (64.4)e | 16.6 (51.8)e | – |
| tmax (h) | 18 | 1.5 (0.5, 4.0)d | 2.0 (0.5, 6.0)e | – |
| Ethinylestradiol | ||||
| Cmax (ng/mL) | 18 | 0.0732 (44.3) | 0.0784 (59.7)d | 1.09 (0.94–1.27) |
| AUC0–last (ng·h/mL) | 18 | 0.714 (57.4) | 1.15 (43.8)d | 1.43 (1.15–1.77) |
| AUC0–inf (ng·h/mL) | 18 | 0.962 (28.4)f | 1.41 (35.1)g | –h |
| t1/2 (h) | 18 | 15.9 (40.9)e | 24.8 (63.4)e | – |
| tmax (h) | 18 | 1.00 (0.5, 2.0) | 1.50 (1.0, 47.5)d | – |
| Levonorgestrel | ||||
| Cmax (ng/mL) | 18 | 3.17 (30.7) | 3.43 (47.3)d | 1.19 (1.00–1.42) |
| AUC0–last (ng·h/mL) | 18 | 52.9 (49.6) | 77.5 (51.5)d | 1.56 (1.33–1.83) |
| AUC0–inf (ng·h/mL) | 18 | 64.0 (53.0)i | 102 (40.6)j | –h |
| t1/2 (h) | 18 | 38.5 (38.5)e | 46.6 (40.4)k | – |
| tmax (h) | 18 | 1.51 (1.0, 4.0) | 1.50 (1.0, 47.5)d | – |
Table adapted from Xiao et al. [47] and Liao et al. [48]
%CV percent coefficient of variation, AUC area under the concentration–time curve, AUC0–72h AUC from time 0 to 72 h, AUC0–96h AUC from time 0 to 96 h, AUC0–inf AUC from time 0 extrapolated to infinity, AUCτ,ss AUC over a dosing interval τ (12 h) at steady state, Cmax maximum plasma concentration, Cmax,ss maximum plasma concentration during a dosing interval at steady state, CYP cytochrome P450, DDI drug–drug interaction, NA not applicable, PK, pharmacokinetic, t1/2 elimination half-life, TEAE treatment-emergent adverse event, tmax time to maximum concentration, tmax,ss time to maximum concentration at steady state
aFor tmax, data are reported as median (minimum, maximum)
bAUC0–inf is not reported because percent of extrapolated AUC was < 20% for ≤ 1 patient
cThe t1/2 is not reported because of uncertainty in the reliability of t1/2 estimation
dn = 17
en = 16
fn = 11
gn = 12
hAUC0–inf geometric mean ratio for oral contraceptives were not calculated because ethinylestradiol AUC0–inf was not accurately determined owing to the high (> 20%) percentage of extrapolation in 7 out of 18 patients when oral contraceptives were dosed alone and 5 out of 17 patients when oral contraceptives were dosed with rucaparib
in = 10
jn = 7
kn = 15